Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer, accounting for approximately 90% of all cases.1 RCC encompasses several subtypes, including clear cell RCC (ccRCC), papillary RCC, and chromophobe RCC, among others. Among these subtypes, ccRCC is the most prevalent form.2 RCC is associated with a poor prognosis, particularly in metastatic cases, with a median survival of approximately 13 months and a 5-year survival rate less than 10%.2
In the United States alone, the estimated number of RCC cases diagnosed in 2018 was 65,340, and the estimated number of deaths attributed to the disease was 14,970.3 In 2020, more than 400,000 new cases of RCC were diagnosed, and approximately 170,000 deaths were reported worldwide.1
As our understanding of the disease has evolved, so has our approach to its treatment. In recent years, pharmacotherapy has played a crucial role in the management of advanced RCC, offering targeted therapies that have revolutionized patient outcomes. This article provides an overview of pharmacologic treatments approved by the US Food and Drug Administration (FDA) for RCC, including dosage, administration, use in special populations, adverse effects, and treatment complications.
Renal Cell Carcinoma Overview
RCC is characterized by the uncontrolled growth of malignant cells in the renal tubules of the kidney. Common symptoms of RCC include hematuria (blood in the urine), flank pain, a palpable mass, and weight loss. The disease is staged based on tumor size (stages 1 and 2),4 lymph node involvement (stage 3), and metastasis (stage 4).4 Early-stage RCC can often be treated with surgical resection, while advanced or metastatic disease requires systemic therapy.
Management of Renal Cell Carcinoma: Pharmacotherapy
In the management of advanced or metastatic RCC, pharmacotherapy plays a crucial role as the primary treatment approach.5 Systemic medications are used to control the growth and spread of cancer cells in advanced or metastatic RCC.5 Targeted therapies and immune checkpoint inhibitors are commonly employed in RCC treatment.5,6
These pharmacotherapeutic agents have demonstrated effectiveness in inhibiting cancer cell growth and enhancing the body’s immune response against cancer cells.5,6 Close collaboration between patients and healthcare providers is important to monitor treatment response, manage side effects, and optimize the pharmacotherapy regimen for each patient with RCC.5
Several classes of drugs are commonly used in the pharmacological management of RCC.
Immune Checkpoint Inhibitors
Immune cells, like T cells, and certain cancer cells possess checkpoint proteins on their surfaces, and these proteins serve to regulate immune responses.7 However, when cancer cells have an abundance of these proteins, the cells can evade destruction by T cells. To address this, immune checkpoint inhibitors are employed to obstruct these proteins, thereby enhancing the ability of T cells to attack and eliminate cancer cells. This treatment approach has proven beneficial for patients with advanced RCC that cannot be surgically removed.
CTLA-4 Inhibitor Therapy
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a protein found on the surface of T cells, plays a crucial role in regulating immune responses within the body.7 By binding to a protein known as B7 on cancer cells, CTLA-4 prevents T cells from attacking and eliminating those cancerous cells. However, CTLA-4 inhibitors can disrupt this interaction by attaching to CTLA-4 and freeing the T cells to effectively target and destroy cancer cells. One notable example of a CTLA-4 inhibitor is ipilimumab.7
Ipilimumab, a commonly used CTLA-4 inhibitor, is often administered in combination with other immunotherapy agents or targeted therapies for patients with advanced or metastatic RCC who may not be suitable candidates for surgery or who have not responded to other treatments.8,9
Clinical studies have demonstrated promising outcomes with CTLA-4 inhibitor therapy in RCC. For example, combination therapy with ipilimumab and nivolumab (a programmed cell death 1 [PD-1] inhibitor; see below) was associated with improved overall survival and response rates compared with previous standard-of-care treatments.10 These findings have led to the approval of ipilimumab in combination with nivolumab as a first-line treatment for advanced RCC.
Dosing and Administration
The recommended dosage of ipilimumab in combination with nivolumab for the treatment of advanced RCC is 1 mg/kg intravenously (IV) every 3 weeks for 4 doses. After completing 4 doses of combination therapy, nivolumab should be continued as a single agent until intolerable toxicity or disease progression occurs.11
Like other immunotherapies, CTLA-4 inhibitor therapy can be associated with potential adverse effects, including immune-related adverse events (irAEs).12 These adverse events occur as a result of immune system activation and can affect numerous organs and systems. Common irAEs include fatigue, diarrhea, rash, itching, colitis (inflammation of the colon), and endocrine-related side effects such as thyroid dysfunction or adrenal insufficiency. More severe irAEs — such as hepatitis, pneumonitis, and neurologic toxicities — can also occur, although they are reported less frequently.13
Ipilimumab is a medication that is not anticipated to exhibit significant pharmacokinetic drug-drug interactions due to its minimal metabolism by drug-metabolizing enzymes such as CYP450.14
Certain contraindications and precautions should be considered when using CTLA-4 inhibitors for RCC. These may include:
- Pre-existing autoimmune diseases. Patients with pre-existing autoimmune conditions, such as rheumatoid arthritis or inflammatory bowel disease, may require careful evaluation and monitoring due to the potential exacerbation of these conditions.15
- Severe organ dysfunction. Individuals with severe liver or kidney impairment may require dose adjustments or alternative treatment approaches, as CTLA-4 inhibitors can affect organ function.16
- Pregnancy and breastfeeding. As the safety of CTLA-4 inhibitors during pregnancy and lactation has not been established, these agents are generally not recommended for use in these situations.17
PD-1 and PD-L1 inhibitor therapy
- PD-1 and PD-L1 (programmed death-ligand 1) inhibitor therapy has emerged as a beneficial treatment modality for RCC. The PD-1/PD-L1 pathway plays a crucial role in regulating immune responses, with PD-1 on T cells and PD-L1 on cancer cells inhibiting immune activation. In RCC, the overexpression of PD-L1 by tumor cells allows them to evade immune surveillance. PD-1 and PD-L1 inhibitors disrupt this interaction, enabling T cells to recognize and attack cancer cells.18
- Examples of PD-1 inhibitors used in RCC treatment include nivolumab and pembrolizumab, while avelumab is a PD-L1 inhibitor that is commonly utilized for this condition. These drugs have demonstrated efficacy in advanced RCC, either as single agents or in combination with other therapies.19
Dosing and Administration
The recommended dosage of nivolumab as a single agent for the treatment of advanced RCC is 240 mg IV over a 30-minute period every 2 weeks until there is evidence of disease progression or unacceptable levels of toxicity.20 The recommended dosage of nivolumab in combination with cabozantinib for the first-line treatment of advanced RCC is 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks plus cabozantinib 40 mg orally once daily until disease progression or unacceptable toxicity.21
Although PD-1/PD-L1 inhibitor therapy offers potential benefits, it is associated with irAEs including fatigue, rash, diarrhea, colitis, pneumonitis (lung inflammation), hepatitis (liver inflammation), and endocrine-related adverse effects such as thyroid dysfunction or adrenal insufficiency. Prompt recognition and management of irAEs are crucial for optimizing treatment outcomes.22
- Immunosuppressive drugs. Concurrent use of immunosuppressive medications, such as corticosteroids (eg, prednisone), may counteract the therapeutic effects of PD-1/PD-L1 inhibitors. Immunosuppressive agents can suppress the immune response, which is the opposite of what the immunotherapy aims to achieve. However, in some cases, such as the management of irAEs, short-term use of corticosteroids may be necessary.23
- Vaccinations. Live vaccines, such as the measles, mumps, and rubella (MMR) vaccine or the varicella-zoster (chickenpox) vaccine, should generally be avoided in patients undergoing treatment with PD-1/PD-L1 inhibitors. These vaccines contain live viruses that may cause severe infections in individuals with a compromised immune system. However, non-live vaccines, such as the flu shot or inactivated vaccines, are generally safe and recommended for patients undergoing immunotherapy.24
Certain contraindications and precautions should be considered when using PD-1/PD-L1 inhibitors in patients with RCC. These may include:
- Pre-existing autoimmune diseases. Patients with pre-existing autoimmune conditions, such as rheumatoid arthritis or systemic lupus erythematosus, may require careful evaluation and monitoring due to the potential exacerbation of these conditions.25
- Severe organ dysfunction. Individuals with severe liver or kidney impairment may need dose adjustments or alternative treatment approaches, as PD-1/PD-L1 inhibitors can affect organ function.26
- Pregnancy and breastfeeding. The safety of PD-1/PD-L1 inhibitors during pregnancy and lactation has not been established, and caution is advised when considering the use of these agents in this setting.27
Interleukin therapy, specifically interleukin-2 (IL-2), has been used in the treatment of RCC.28 Interleukins are naturally occurring proteins that play a crucial role in regulating immune responses. IL-2 is a type of cytokine that stimulates the growth and activation of various immune cells, including T cells and natural killer (NK) cells, to target and destroy cancer cells.
High-dose IL-2 therapy has been used as an immunotherapy option for patients with advanced RCC. It can induce durable responses leading to long-term remission in a subset of patients.28 However, it is important to note that IL-2 therapy is associated with significant toxicities and is typically limited to patients with good organ function and performance status.
Dosing and Administration
The recommended dosage of high-dose IL-2 is 600,000 to 720,000 IU/kg administered every 8 hours over 15 doses. This regimen has an overall response rate of 15% to 20%, but it is associated with significant toxicities that affect multiple organ systems.29 High-dose IL-2 should still be considered a first-line therapy in patients with metastatic RCC who have an overall good performance status.30
The adverse effects of IL-2 therapy can be severe due to its potent immune-stimulating properties. Common adverse effects include flu-like symptoms such as fever, chills, fatigue, and muscle aches. Additionally, IL-2 therapy can cause capillary leak syndrome, leading to fluid retention, low blood pressure, and organ dysfunction.31 Other potential adverse effects include liver toxicity, kidney dysfunction, heart rhythm abnormalities, and neurologic symptoms. Close monitoring and specialized care in an experienced medical setting are crucial during IL-2 therapy to manage and mitigate these adverse effects.32
- Tumor necrosis factor inhibitors. Tumor necrosis factor (TNF) inhibitors, such as infliximab or adalimumab, are used to treat autoimmune conditions like rheumatoid arthritis and inflammatory bowel disease. These medications target TNF, which can influence the production of interleukins. The use of TNF inhibitors may affect the levels or activity of interleukins, leading to potential interactions.33
- Immunosuppressive drugs. Medications that suppress the immune system, such as corticosteroids (eg, prednisone) or calcineurin inhibitors (eg, cyclosporine), can modulate the activity of interleukins. These agents may interfere with the production or action of interleukins, affecting the immune response.34
Contraindications for IL-2 therapy in patients with RCC include:
- Pre-existing heart or lung conditions. IL-2 therapy can put a strain on the cardiovascular and respiratory systems. Patients with significant heart or lung diseases may not be suitable candidates for IL-2 therapy.35
- Organ dysfunction. Patients with impaired liver or kidney function may require careful evaluation and monitoring during IL-2 therapy.35
Targeted therapy is a specialized form of treatment that employs drugs or substances designed to selectively identify and combat particular cancer cells. In the case of advanced RCC, targeted therapy involving antiangiogenic agents is utilized. These agents work by inhibiting the formation of blood vessels within a tumor, ultimately leading to its starvation, cessation of growth, or even shrinkage. Targeted therapies can be classified based on their mechanisms of action and the molecular targets they specifically inhibit.
The following is a brief classification of targeted therapies commonly used in the management of RCC.
Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors (TKIs) target specific enzymes called tyrosine kinases, which play a crucial role in signaling pathways involved in cancer cell growth and angiogenesis.
These inhibitors target the vascular endothelial growth factor (VEGF) pathway, which promotes the formation of new blood vessels that supply nutrients to tumors. VEGF inhibitors, including bevacizumab, interfere with VEGF signaling and inhibit angiogenesis. These inhibitors are used in the treatment of numerous cancers.36
Although VEGF inhibitors can be effective in their intended use, they can also have adverse effects, potential drug interactions, and contraindications. Examples of VEGF inhibitors used for the treatment of RCC include sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib plus everolimus combination therapy.
Dosing and Administration
The recommended dosage of bevacizumab in combination with interferon alfa for the treatment of advanced RCC is 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. A phase 1b/2 clinical trial of pembrolizumab with bevacizumab in patients with advanced RCC showed that the combination of pembrolizumab 200 mg and bevacizumab 15 mg/kg given every 3 weeks is safe and active in patients with metastatic RCC. Similarly, the recommended dosage of pembrolizumab in combination with axitinib for the treatment of RCC is 200 mg IV over 30 minutes every 3 weeks.37
- Hypertension. VEGF inhibitors can cause an increase in blood pressure. Regular monitoring of blood pressure is important with this treatment, and antihypertensive medications may be needed to manage hypertension.38
- Bleeding. VEGF inhibitors can interfere with blood clotting and increase the risk of bleeding or hemorrhage. Patients with a history of bleeding disorders or those taking anticoagulant medications may be at increased risk of bleeding.39
- Proteinuria. Some VEGF inhibitors can cause protein leakage in the urine (proteinuria). Monitoring kidney function is important, and dose adjustments may be necessary if significant proteinuria occurs.40
- Impaired wound healing. VEGF is involved in the process of wound healing, so VEGF inhibitors can potentially impair wound healing. This can be particularly relevant for patients undergoing surgery or those with open wounds.41
- Gastrointestinal effects. VEGF inhibitors can cause side effects like diarrhea, nausea, and vomiting. These symptoms should be managed appropriately to prevent dehydration and electrolyte imbalances.41
- Anticoagulants and antiplatelet drugs. VEGF inhibitors can increase the risk of bleeding. Concurrent use with anticoagulants (eg, warfarin, heparin) or antiplatelet drugs (eg, aspirin, clopidogrel) can further increase this risk.42
- Other medications affecting blood pressure. VEGF inhibitors can cause hypertension. Concurrent use of medications that can increase blood pressure, such as certain immunosuppressant agents or nonsteroidal anti-inflammatory drugs (NSAIDs), may worsen hypertension.42
- Hemorrhagic disorders. Patients with active bleeding, recent bleeding events, or known bleeding disorders may be at increased risk of bleeding complications with VEGF inhibitors.39
- Recent major surgery. VEGF inhibitors may impair wound healing; therefore, they are generally contraindicated in the immediate postoperative period or in patients with unhealed surgical wounds.41
- Pregnancy and breastfeeding. VEGF inhibitors may have harmful effects on the developing fetus or nursing infant. They are generally contraindicated during pregnancy and breastfeeding.42
Mammalian target of rapamycin (mTOR) inhibitors target the mTOR pathway, which is involved in cell growth and proliferation. mTOR inhibitors are a class of medications used in the treatment of numerous conditions, including certain types of cancer and immune-mediated diseases. These agents work by inhibiting mTOR, a protein that regulates cell growth, proliferation, and survival. These inhibitors, such as everolimus and temsirolimus, help suppress the growth of cancer cells in RCC.43 Everolimus and temsirolimus are indicated for the treatment of advanced RCC.
Dosing and Administration
The recommended dosage of everolimus is 10 mg orally once daily.44 The recommended dosage of temsirolimus for advanced RCC is 25 mg IV infusion over a 30- to 60-minute period once a week.45
- Immunosuppression. mTOR inhibitors can suppress the immune system, increasing the risk of infections. Patients should be monitored for signs of infection and may require prophylactic treatment or adjustments in immunosuppressive regimens.46
- Metabolic disturbances. mTOR inhibitors can cause metabolic changes, such as hyperlipidemia (elevated blood lipids), hyperglycemia (high blood sugar), and changes in electrolyte levels. Monitoring of lipid profiles, blood glucose, and electrolytes is important during treatment.47
- Gastrointestinal effects. Common side effects include diarrhea, nausea, vomiting, and stomatitis (inflammation of the mouth and lips). These symptoms should be managed appropriately to prevent dehydration and nutritional deficiencies.47
- Skin reactions. mTOR inhibitors can cause skin problems such as rashes, acne-like lesions, and photosensitivity. Sun protection measures and proper skin care are important to minimize these effects.48
- Interstitial lung disease. Rarely, mTOR inhibitors have been associated with interstitial lung disease, characterized by inflammation and scarring of lung tissue.47 Patients should be monitored for respiratory symptoms such as cough, dyspnea (shortness of breath), and fever.49
- Immunosuppressants. Concurrent use of other immunosuppressive medications, such as corticosteroids or calcineurin inhibitors, may increase the risk of immunosuppression and its associated complications. Dose adjustments and careful monitoring are necessary when combining these medications.50
- CYP3A4 inducers and inhibitors. mTOR inhibitors, such as everolimus, are metabolized by the liver enzyme CYP3A4. Co-administration with strong CYP3A4 inducers (eg, rifampin) or inhibitors (eg, ketoconazole) can affect the levels of mTOR inhibitors in the body. Dose adjustments may be required to maintain appropriate drug levels.51
- Hypersensitivity. Patients with known hypersensitivity to mTOR inhibitors or their components should not take these medications.
- Pregnancy and breastfeeding. mTOR inhibitors may harm the developing fetus or nursing infant. These agents are generally contraindicated during pregnancy and breastfeeding.52
Clinical Trials and Pharmacologic Treatments Under Investigation for RCC
Clinical trials play a crucial role in advancing the field of RCC treatment by investigating new therapies and treatment combinations. The following are some examples of ongoing clinical trials that aim to develop new treatments for RCC.
Combinations of Pembrolizumab With Other Drugs
A phase 2 clinical trial is evaluating the use of pembrolizumab, an immune checkpoint inhibitor, in combination with lenvatinib, a targeted therapy. The trial aims to assess the effectiveness and safety of this combination in patients with advanced RCC (ClinicalTrials.gov Identifier: NCT02501096). Pembrolizumab enhances the immune response against cancer cells, and lenvatinib targets specific signaling pathways involved in tumor growth.53
A phase 3 clinical trial of pembrolizumab with ziv-aflibercept (ClinicalTrial.gov Identifier: NCT02298959) is currently being conducted to investigate the combination of these 2 drugs in the treatment of advanced RCC. So far, the trial has demonstrated an acceptable safety profile with antitumor activity in solid tumors.53
Survivin is a protein that is overexpressed in RCC and is associated with a poor prognosis. Survivin inhibitors are being investigated as a potential treatment for RCC.54 YM155 has been shown to inhibit the growth of RCC cells and enhance the effectiveness of other anticancer drugs.54 Survivin inhibitors are still in the early stages of development and have not yet been approved for the treatment of RCC. However, preclinical studies have shown promising results, and clinical trials are ongoing to investigate the safety and efficacy of survivin inhibitors in the treatment of RCC.
Myeloid cell leukemia-1 (MCL-1) is a protein that plays a crucial role in regulating cell survival and preventing apoptosis (programmed cell death). In RCC, MCL-1 is often overexpressed, leading to increased cell survival and resistance to traditional cancer treatments such as chemotherapy and radiation therapy.55
Researchers are actively exploring the use of MCL-1 inhibitors as a potential treatment strategy for RCC. By inhibiting MCL-1, these agents aim to selectively target and induce apoptosis in cancer cells, thereby overcoming the resistance mechanisms associated with MCL-1 overexpression.55
The preclinical data on S63845 in RCC is encouraging, suggesting its potential as a therapeutic option. However, it is important to note that the development of MCL-1 inhibitors for RCC is still in the early stages, and more research is needed to determine the safety, efficacy, and optimal use of these agents in clinical settings. Clinical trials are essential to further investigate the potential of MCL-1 inhibitors for RCC treatment.
Hypoxia-inducible factor-2 alpha (HIF-2α) is a protein that plays a critical role in regulating cellular responses to low oxygen levels (hypoxia). In RCC, HIF-2α is frequently overexpressed, and its dysregulation is associated with poor prognosis and tumor progression.
Researchers are actively studying HIF-2α inhibitors as a potential targeted therapy for RCC.56 Their aim is to develop inhibitors that can specifically target HIF-2α and disrupt its function, thereby inhibiting the growth and survival of RCC cells.
One HIF-2α inhibitor that has shown promise in clinical trials is MK-6482 (also known as belzutifan). MK-6482 is an oral, small molecule inhibitor that selectively targets HIF-2α, preventing its binding to DNA and reducing the expression of genes associated with tumor growth and angiogenesis (formation of new blood vessels to support tumor growth).56
A phase 1 clinical trial is currently underway to investigate the use of a novel immunotherapy drug called a bispecific T-cell engager (BiTE) for the treatment of RCC (ClinicalTrials.gov Identifier: NCT03517488). BiTE is a type of immunotherapy that is designed to engage and activate the body’s immune system to target and destroy cancer cells.57
BiTEs are engineered antibodies that have the ability to bind to 2 different cell types simultaneously. In the case of RCC, the BiTE is designed to bind to T cells, which are a type of immune cell, as well as to cancer cells expressing specific targets on their surface.57
Additionally, researchers will evaluate the pharmacokinetics and pharmacodynamics of the BiTE, which involves studying how the drug is absorbed, distributed, metabolized, and eliminated, as well as its mechanism of action and effect on the immune response.
In conclusion, RCC is the most common type of kidney cancer, accounting for the majority of cases. Despite advancements in our understanding of the disease, RCC still carries a poor prognosis — particularly in metastatic cases — with low survival rates. However, pharmacotherapy has significantly improved the management of advanced or metastatic RCC, with targeted therapies and immune checkpoint inhibitors playing a pivotal role.
These pharmacologic treatments have revolutionized patient outcomes by inhibiting cancer cell growth and enhancing the body’s immune response against cancer cells. Close collaboration between patients and healthcare providers is essential for monitoring treatment response, managing side effects, and optimizing the pharmacotherapy regimen.
RCC Treatment Guidelines
Several guidelines for RCC treatment are currently available to aid in clinical decision-making.
- The National Comprehensive Cancer Network (NCCN) provides guidelines for the management of RCC. The guidelines recommend partial nephrectomy or radical nephrectomy for stage II renal tumors. For stage IV RCC, the guidelines recommend radical nephrectomy plus surgical metastasectomy, with consideration of first-line systemic therapy if relapse occurs. Adjuvant and neoadjuvant treatment should not be considered outside of clinical trials.57
- The American Cancer Society (ACS) offers comprehensive information regarding treatment options for RCC. These options include surgery, targeted therapy, immunotherapy, and radiation therapy. It is important to note that the ACS emphasizes the need for individualized treatment decisions based on various factors, such as stage and grade of the cancer, the patient’s overall health, and other pertinent considerations.58
- The 2017 Clinical Practice Guidelines for the Treatment of Renal Cell Carcinoma provides a systematic review and critical evaluation of current clinical practice guidelines for the treatment of RCC. The guidelines recommend the use of partial nephrectomy, radical nephrectomy, and active surveillance for the management of localized RCC. For advanced RCC, the guidelines recommend the use of targeted therapy, immunotherapy, and combination therapy.59
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Sagar Desai, MPharm, PhD